The Importance of Insulin Timing in Type 1 Diabetes

Data:

The Rationale for Timing of the premeal insulin administration - In type 1 diabetes, very little, if any, endogenous insulin is available to handle the carbohydrate load which very rapidly enters the circulation after the start of a meal. In non-diabetic individuals, a complex array of physiological events occurs prior to eating (often called the cephalic phase of insulin secretion) which prepares the pancreas for immediate release of preformed insulin when any meal related increase in blood glucose occurs. This rapid insulin secretion prepares the tissues (primarily muscle and liver) to take up glucose very rapidly and thereby prevent severe hyperglycemia in the postprandial state. Since significant absorption of all short acting insulins (e.g. insulin Lispro, Aspart, or Glulisine) from the subcutaneous tissue does not occur for 15 minutes following injection (26), this delay often results in postprandial hyperglycemia. If the patient happens to be hypoglycemic prior to the meal, this delay can be advantageous, but if he/she is hyperglycemic, then severe postprandial hyperglycemia may result. A rationale solution to this problem would be to time the short acting insulin injection based on the premeal blood glucose, but aside from our one pilot study addressing this strategy, no clinical study has been published supporting this approach. Our grant application is designed to correct this deficiency and provide the scientific data to support this addition to intensive insulin therapy.

We studied the effect of Timing a fixed dose of rapid acting insulin Lispro (Humalog™) in twelve type 1 diabetic subjects who were all made hyperglycemic prior to a standardized diabetic meal (11). In all studies, the dose of insulin of 0.15U/kg (~10 units) remained constant and represented a typical dose utilized by type 1 diabetic patients prior to an evening meal. Each of the twelve diabetic volunteers participated in all four study arms (48 total studies). The insulin Lispro was given at the following times: 1) 30 minutes prior to meal time (-30 minutes), 2) 15 minutes prior to the meal time (-15 minutes), 3) at the meal (0 minutes), and 4) 15 minutes after the meal was begun (+15 minutes). As is shown in Figure 1, a normal postprandial glucose excursion was observed when the insulin was taken 15 minutes prior to the meal. No postprandial excursion was observed when the insulin was taken 30 minutes prior to the meal. This is the desirable outcome in a hyperglycemic individual. Of particular interest is the fact that when the insulin :Lispro was taken right at mealtime (which is the most common pattern in type 1 diabetic patients), significant postprandial hyperglycemia was observed. Figure 2 provides the integrated postprandial glucose excursion (above and below baseline) over the entire 5½ hour study and reflects the data in Figure 1. This study strongly supports the injection of insulin Lispro at least 15 minutes prior to the meal when premeal hyperglycemia is present.

To be certain that the absorption of insulin Lispro was not different between the four studies which might account for the difference in postprandial glucose excursion; we measured free insulin levels during all four research studies. As is shown in Figure 3, when the insulin excursion concentrations are superimposed on each other for each study, no difference in insulin absorption occurred between the four insulin administration protocols. This data strongly supports the concept that timing of the insulin injection prior to the meal has a major effect on glucose kinetics following a meal. Utilization of Timing in an Intensive Insulin Therapy regimen should have a major beneficial effect of suppressing postprandial hyperglycemia and reducing A1C.

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